GLP-1 plays a protective role in hippocampal neuronal cells by activating cAMP-CREB-BDNF signaling pathway against CORT+HG-induced toxicity.

Major depressive disorder (MDD) with diabetes mellitus (DM) significantly reduces the quality of the patient's life, and currently, there is no effective treatment. This study explored the feasibility of Glucagon-like peptide-1 (GLP-1) in treating MDD combined with DM. The protective effects of GLP-1 on mouse hippocampal neuronal cell line HT22 cultured with corticosterone (CORT) and high glucose (HG) were assessed. HT22 cells were cultured with CORT + HG to construct a cell model of MDD combined with DM. Cell viability and cell apoptosis/necrocytosis were detected by CCK-8 assay and flow cytometry/confocal laser scanning microscopy, respectively, after treatment with GLP-1. In addition, BDNF and neurotransmitter levels, lactic dehydrogenase (LDH) and glucose levels, and proteins of cAMP-CREB-BDNF signal pathway in the culture supernatants were measured through an enzyme-linked immunosorbent assay and colorimetric assays and Western blot, respectively. The ideal intervention combination to construct a cell model of MDD combined with DM was CORT 200 µM and HG 50 mM for 48 h. After treatment of 50 nM GLP-1 for 48 h, the model+50 nM GLP-1 group's apoptosis and necrocytosis rates and LDH and glucose concentrations in the culture supernatants decreased significantly compared with the model group. However, the BDNF, 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), PKA, p-CREB, and p-Trkb concentrations in the culture supernatants increased significantly. GLP-1 functioned against CORT + HG-induced toxicity by activating the cAMP-CREB-BDNF signaling pathway in hippocampal neuronal cells.

The impact of oxygen on Ga doped ZnO film.

The Ga doped ZnO (GZO) film is one of the promising alternative films to replace ITO film, but its properties suffer from degradation when it is deposited under oxygen-rich conditions. This degradation has been investigated by depositing the films under different oxygen partial pressures. XRD results showed that all GZO films had wurtzite structure and the lattice parameter-c contracted when oxygen was introduced into the argon deposition atmosphere, but the parameter-c nearly remained constant when oxygen partial pressures were further increased. The contraction of parameter-c was caused by the increasing concentrations of VZn (Zn vacancy). It was the first time to observe that the impurity phase of Ga2Zn6O9 appeared and disappeared in GZO films during the increase of oxygen partial pressures. Analogously, conductivity decayed and optical bandgap decreased abruptly as oxygen was introduced, which enhanced self-compensation of donors and acceptors. The energy band structures of GZO and ZnO films were determined by using UPS, and the results showed that oxygen had little effect on the electron affinity of the GZO film, but a significant difference in electron affinity between the ZnO and GZO films was observed. This result indicated that although the electron affinity of ZnO could be effectively tuned by doping with Ga, it remained quite stable for GZO under oxygen-rich conditions.

Association of Social Isolation and Loneliness With Incident Heart Failure in a Population-Based Cohort Study.

BACKGROUND: Social isolation and loneliness have emerged as important risk factors for cardiovascular diseases, particularly during the coronavirus disease pandemic. However, it is unclear whether social isolation and loneliness had independent and joint associations with incident heart failure (HF). OBJECTIVES: This study sought to examine the association of social isolation, loneliness, and their combination with incident HF. METHODS: The UK Biobank study is a population-based cohort study. Social isolation and loneliness were assessed using self-reported questionnaires. HF cases were identified by linking hospital records and death registries. The weighted polygenic risk score associated with HF was calculated. RESULTS: Among the 464,773 participants (mean age: 56.5 ± 8.1 years, 45.3% male), 12,898 incident HF cases were documented during a median follow-up of 12.3 years. Social isolation (most vs least: adjusted HR: 1.17; 95% CI:1.11-1.23) and loneliness (yes vs no: adjusted HR: 1.19; 95% CI: 1.11-1.27) were significantly associated with an increased risk of incident HF. The association between an elevated risk of HF and social isolation was modified by loneliness (Pinteraction = 0.034). A gradient of association between social isolation and the risk of incident HF was found only among individuals without loneliness (Ptrend < 0.001), but not among those with loneliness (Ptrend = 0.829). These associations were independent of the genetic risk of HF. CONCLUSIONS: Social isolation and loneliness were independently associated with a higher likelihood of incident HF regardless of genetic risk. The association between social isolation and incident HF was potentially modified by loneliness status.

Predictive Value Analysis of Serum Ig A, Ig G, and TNF-α in Recurrence of Multiple Myeloma.

Objective: The study is aimed at analyzing the predictive value of serum Ig A, Ig G, and TNF-α in the recurrence of multiple myeloma (MM). Methods: 136 patients with MM treated in our hospital from January 2010 to January 2017 were followed up for 5 years. Finally, 100 patients who met the inclusion and exclusion criteria and had the complete follow-up visit were selected as the study subjects, with the recurrence of MM as endpoint event, and the observation was taken until the occurrence of endpoint event in patients or the termination of this study. They were divided into the recurrence group (RG) and the nonrecurrence group (NRG) according to whether the endpoint event occurred. The venous blood of patients was collected at the first diagnosis and subsequent visit (at the time of recurrence or termination of the study) to measure the Ig A and Ig G using a full automatic special protein analyzer and the TNF-α level by enzyme-linked immunosorbent assay. The data obtained in this study were analyzed by univariate analysis to choose the factors with difference in statistical significance to draw the ROC curve, and the areas under the curve (AUC) were recorded to analyze the potential mechanism of Ig A, Ig G, and TNF-α in predicting the recurrence of MM. Results: After follow-up visit, there were 62 patients with recurrence (62.0%) and 38 patients without recurrence (38.0%), with no obvious difference in gender, age, body weight, and immune classification between the two groups (P > 0.05). Compared with the NRG, the levels of soluble interleukin-2 receptor (sIL-2R) and ß 2-microglobulin (ß 2-MG) in the RG at the first diagnosis were distinctly higher (P < 0.001); the levels of Ig A, Ig G, and TNF-α in the RG at the first diagnosis were visibly higher (P < 0.05); and the levels of Ig A, Ig G, and TNF-α in the RG at the subsequent visit were clearly higher (P < 0.05). There was a correlation between Ig G, Ig A, and TNF-α and ß 2-MG at the first diagnosis and the subsequent visit (P < 0.05); there was a correlation between Ig G and TNF-α, and sIL-2R at the first diagnosis and the subsequent visit (P < 0.05); and there was a correlation between Ig A and sIL-2R at the subsequent visit (P < 0.05). The AUC of Ig G, Ig A, and TNF-α in predicting the MM at the first diagnosis were 0.772, 0.776, and 0.778, respectively. Conclusion: The serum Ig A, Ig G, and TNF-α had a predictive value in the recurrence of MM, and TNF-α was correlated with sIL-2R and ß 2-MG, with the highest AUC and the best predictive value.

Targeting the TXNIP-NLRP3 interaction with PSSM1443 to suppress inflammation in sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD), a deadly symptom in sepsis patients, is mainly caused by cardiovascular inflammation. However, it remains unclear how systemic inflammation triggers and aggravates cardiovascular inflammation in the pathogenesis of SIMD. This study found that proinflammatory cytokines and H2 O2 concentrations were significantly induced in SIMD-mice. In particular, a microarray analysis of CD63+ exosomes isolated from sham- and SIMD-monocytes revealed a significant induction of thioredoxin-interacting protein (TXNIP) and NLR family pyrin domain-containing 3 (NLRP3). We proved that oxidative stress caused the disassociation of the TXNIP-TRX2 (thioredoxin 2) complex and the assembly of the TXNIP-NLRP3 complex. In addition, this finding showed that the latter complex could be embedded into CD63+ exosomes and traffic from monocytes to the resident heart macrophages, where it activated caspase-1 and cleaved inactive interleukin 1ß (IL-1ß) and IL-18. Furthermore, using an amplified luminescent proximity homogeneous assay (Alpha) with GST-TXNIP and His-NLRP3, we obtained a small molecule named PSSM1443 that could disrupt the TXNIP-NLRP3 interaction in vitro, impairing NLRP3 downstream events. Of note, after administering PSSM1443 to the SIMD-mice, we found the small molecule could significantly suppress the activation of caspase-1 and the cleavage of pro-IL-1ß and pro-IL-18, reducing inflammation in the SIMD-mice. Collectively, our results reveal that monocyte-derived exosomes harbor the overexpressed TXNIP-NLRP3 complex, which traffics from circulating monocytes to local macrophages and promotes the cleavage of inactive IL-1ß and IL-18 in the macrophages, aggravating cardiovascular inflammation. PSSM1443 functions as an inhibitor of the TXNIP-NLRP3 complex and its administration can decrease inflammation in SIMD-mice.

Characterization of Sputtered CdTe Thin Films with Electron Backscatter Diffraction and Correlation with Device Performance.

The performance of polycrystalline CdTe photovoltaic thin films is expected to depend on the grain boundary density and corresponding grain size of the film microstructure. However, the electrical performance of grain boundaries within these films is not well understood, and can be beneficial, harmful, or neutral in terms of film performance. Electron backscatter diffraction has been used to characterize the grain size, grain boundary structure, and crystallographic texture of sputtered CdTe at varying deposition pressures before and after CdCl2 treatment in order to correlate performance with microstructure. Weak fiber textures were observed in the as-deposited films, with (111) textures present at lower deposition pressures and (110) textures observed at higher deposition pressures. The CdCl2-treated samples exhibited significant grain recrystallization with a high fraction of twin boundaries. Good correlation of solar cell efficiency was observed with twin-corrected grain size while poor correlation was found if the twin boundaries were considered as grain boundaries in the grain size determination. This implies that the twin boundaries are neutral with respect to recombination and carrier transport.

Inhibitory effects and molecular mechanisms of garlic organosulfur compounds on the production of inflammatory mediators.

SCOPE: Garlic is used for both culinary and medicinal purposes by many cultures. The garlic organosulfur compounds (GOSCs) are thought to be bioactive components. This study aims to clarify the antiinflammatory effects and molecular mechanisms of GOSCs in both cell and animal models. METHODS AND RESULTS: RAW264.7 cells were treated with six kinds of GOSCs to screen their influence on cyclooxygenase-2 and inducible nitric oxide synthase expression by Western blotting. Prostaglandin E2 and nitrite were measured by ELISA and Griess reaction, respectively. Cytokines in culture medium were assayed by the multiplex technology. Proteins were detected by Western blotting. Mouse paw edema was induced by LPS. The results revealed that diallyl trisulfide (DATS) was a strongest inhibitor for cyclooxygenase and inducible nitric oxide synthase among GOSCs, and reduced the levels of LPS-induced IL-6, IL-10, IL-12(p70), KC, MCP-1, and TNF-α. Cellular signaling analysis revealed that DATS downregulated AKT1/TGF-ß-activated kinase-mediated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Furthermore, DATS activated Nrf2-mediated expression of HO-1 and NQO1 and reduced LPS-induced intracellular reactive oxygen species, which may contribute to suppress inflammatory mediator production. Finally, in vivo data demonstrated that DATS attenuated LPS-induced mouse paw edema. CONCLUSION: DATS as a potential inhibitor revealed antiinflammatory effect in both cell and animal models by downregulating AKT1/TGF-ß-activated kinase-mediated NFκB and MAPK signaling pathways.

[Relations between serum homocysteinemia and carotid artery plaques].

OBJECTIVE: To explore the relation between homocysteinemia (HCY) and carotid artery plaque. METHODS: Subjects were derived from a cohort of Kailuan study, which was a community-based and cross-sectional. From June 2010 to June 2011, a total of 5852 subjects were selected from 101 510 working or retired employees at the Tangshan Kailuan Company in 2006 - 2007. Data was extracted from the results of health examination on the employees. Selecting process was carried out by those staff working on the clinical trials on stroke and from the research center of Tiantan Hospital, Capital Medical University. Subjects who were beyond 40 years of age but without histories as previous stroke, transient ischemic attack (TIA) or myocardial infarction were included and identified, to take part in the study through stratified random sampling. Finally, 5440 eligible subjects were enrolled and data from 5377 subjects were analyzed. All the information was obtained through unified questionnaire, blood tests and carotid artery ultrasonography. Multivariate logistic regression was used to analyze the factors related to carotid artery plagues. RESULTS: (1) The baseline results showed that the average age of the subjects (n = 5377) was 55.18 ± 11.78 years old with 3215 as males. All the subjects were divided into three groups by tertiles of HCY, with 1771 subjects in the first quartile group (HCY < 11.00 µmol/L), 1814 in the second quartile group (11.00-16.98 µmol/L) and 1792 in the third quartile group (≥ 16.98 µmol/L). 2300 subjects were identified as having carotid artery plaques. (2) The prevalence rates of carotid artery plaques in the three groups were 29.9%, 43.3% and 55.0% respectively. (3) After multivariable adjustment, the third quartile HCY was still serving as a risk factor, affecting the formation of carotid artery plaques, with the OR values as 1.344 (95%CI: 1.134 - 1.594). CONCLUSION: High HCY was related to the increased prevalence of carotid artery plaque and thus served as a risk factor for carotid artery plaque.

[Study on the inhibit mechanism primarily of extracts from Coptis on clinical resistant the medicine of Staphylococcus aureus].

OBJECTIVE: To discuss the inhibit mechanism primarily of extracts from Coptis on clinical resistant the medicine of Staphylococcus aureus. METHODS: Used SDS-PAGE electrophoresis, spectrophotometry and semiautomatic biochemistry analysis to detect the accumulated concentration of norfloxacin, membranin electrophoretogram and the enzymatic activity in extracellular fluid before and after Coptis extract disposition. RESULTS: The accumulated concentration of medicine norfloxacin within the experiment strains which treated with Coptis extract was clear higher than that of the blank space (P < 0.01); some proteins which molecular weights were in 35 - 38 kDa rebound expressed after Coptis extract treated; The extracellular fluid enzymic activities of resistant Staphylococcus aureus had no significant difference (P > 0.05). CONCLUSION: The inhibit mechanism primarily of extracts from Coptis on clinical resistant the medicine of Staphylococcus aureus is the results of the combined action of various chemical composition and multi-target interaction, and the exact molecular mechanism remains to be further researched.

Expression, purification, and characterization of recombinant human keratinocyte growth factor-2 in Pichia pastoris.

Keratinocyte growth factor-2 (KGF-2) is a member of the fibroblast growth factor family. The full-length human KGF-2 coding sequence, gained by synthesizing, was cloned into the pPICZalphaA vector in frame with the yeast alpha-factor secretion signal under the transcriptional control of the AOX promoter and integrated into Pichia pastoris strain GS115. In shake-flask culture induced with methanol, the rhKGF-2 content was about 17.5% of the total secreted proteins. Under the optimal conditions, stable production of rhKGF-2 around 1.0g/l was achieved. The recombinant protein was purified by heparin affinity chromatography. A preliminary biochemical characterization of purified rhKGF-2 was performed both by Western blot analysis and biological activity analysis, and the result demonstrated that the recombinant KGF-2 was expressed successfully.

Removal of antibiotic resistance of live vaccine strain Escherichia coli MM-3 and evaluation of the immunogenicity of the new strain.

MM-3 was a live vaccine strain candidate for protecting neonatal piglets from diarrhea. Designed in the 1980s, a high degree of protection from colibacillosis was afforded to piglets in a challenge study and field trials. However MM-3 had a drawback of carrying the antibiotic resistance gene (chloramphenicol acetyltransferase gene, cat). The introduction of a host-plasmid balanced lethal system into the vaccine was a good idea to solve the problem. The lambda-Red recombination system was adopted in this study to realize the replacement of cat by aspartate-semialdehyde dehydrogenase gene (asd) in the plasmid pMM085. The new plasmid named pMMASD was introduced into an Escherichia coli strain chi6097 and Salmonella typhimurium chi4072 where the asd gene had been knocked out in their chromosomes. Cultured in an Erlenmeyer flask, expression levels of two antigens K88ac fimbriae and heat-labile enterotoxin B subunit (LTB) in cell lysate were similar among MM-3, chi4072(pMMASD) and chi6097(pMMASD). However, chi4072(pMMASD) possessed the more effective secretion mechanism to transport LTB enterotoxin into culture liquid. The relatively higher stability of pMMASD in Salmonella typhimurium chi4072 than that of pMM085 in MM-3 was determined both in vitro in the absence of selective pressure, and in vivo following oral inoculation. Oral immunization of BALB/c mice with chi4072(pMMASD) or chi6097(pMMASD) was sufficient to elicit IgA responses in mucosal tissues as well as systemic IgG antibody responses to the K88 fimbriae, while MM-3 failed to elicit specific antibody responses to K88 fimbriae in mucosal tissues. Among three live strains, only chi4072(pMMASD) could develop strong humoral responses against LTB enterotoxin. The results suggest that chi4072(pMMASD) is expected to be a promising live vaccine strain.

Construction of a novel Shigella live-vector strain co-expressing CS3 and LTB/STm of enterotoxigenic E.coli.

AIM: To construct and evaluate a polyvalent recombinant vaccine strain Shigella flexneri 2a T32 against enterotoxigenic E.coli (ETEC). METHODS: By using a host-plasmid balanced lethal system based on asd gene, a polyvalent recombinant strain was constructed to highly express CS3 and regularly express fusion enterotoxin of LTB subunit and mutant ST (LTB/STm) in a vaccine strain Shigella flexneri 2a T32 with specific deletion of asd gene. Fimbria CS3 was observed by immunofluorescence and electron microscopy assay. The security of LTB/STm was examined by ileal loop assay and suckling mouse assay. To evaluate this new candidate vaccine, it was compared with a previous vaccine strain in plasmid and protein level, growth assay and immunogenicity in Balb/c mice. RESULTS: The newly constructed vaccine expressed CS3 and grew better than the previously constructed vaccine except for the lower expression of LTB/STm. Serum IgG and mucosal IgA against CS3, LTB, ST, and host lipopolysaccharide (LPS) were produced after immunization of Balb/c mice by oral route with the new strain. The titers were not significantly different from the Balb/c mice with the previous strain. CONCLUSION: This novel candidate diarrheal vaccine can effectively induce serum and mucosal antibody responses against ETEC and Shigella.

[Effects of intermittent normobaric hypoxia training on heart rate variability].

OBJECTIVE: To observe the influences of intermittent normobaric hypoxia (INH) training on heart rate variability (HRV) under hypoxia. METHOD: Eight subjects were trained with INH for 4 weeks (24 d), subjects' HRV level, recorded during exposure to hypoxia (10% O2) before and after the training, were compared and analyzed. RESULT: After the INH training, average of normal to normal Intervals (R-R), standard deviation of normal to normal Intervals (SDNN), total power (TP), high frequency (HF) and low frequency (LF) increased significantly during hypoxia (P<0.05 - P<0.001); normalized low frequency (LFn), normalized high frequency (HFn) and LF/HF showed no significant change. CONCLUSION: 1) INH training can increase subjects' HRV under hypoxia; 2) INH training can not only be used to increase the tolerance of hypoxia, but it is also good for increasing astronaut's flying tolerance under special environment.